Progesterone receptor distribution in the human hypothalamus and its association with suicide

The human hypothalamus modulates mental health by balancing interactions between hormonal fluctuations and stress responses. Stress-induced progesterone release activates progesterone receptors (PR) in the human brain and triggers alterations in neuropeptides/neurotransmitters. As recent epidemiological studies have associated peripheral progesterone levels with suicide risks in humans, we mapped PR distribution in the human hypothalamus in relation to age and sex and characterized its (co-) expression in specific cell types. The infundibular nucleus (INF) appeared to be the primary hypothalamic structure via which progesterone modulates stress-related neural circuitry. An elevation of the number of pro-opiomelanocortin + (POMC, an endogenous opioid precursor) neurons in the INF, which was due to a high proportion of POMC + neurons that co-expressed PR, was related to suicide in patients with mood disorders (MD). MD donors who died of legal euthanasia were for the first time enrolled in a postmortem study to investigate the molecular signatures related to fatal suicidal ideations. They had a higher proportion of PR co-expressing POMC + neurons than MD patients who died naturally. This indicates that the onset of endogenous opioid activation in MD with suicide tendency may be progesterone-associated. Our findings may have implications for users of progesterone-enriched contraceptives who also have MD and suicidal tendencies

Progesterone receptor distribution in the human hypothalamus and its association with suicide

The human hypothalamus modulates mental health by balancing interactions between hormonal fluctuations and stress responses. Stress-induced progesterone release activates progesterone receptors (PR) in the human brain and triggers alterations in neuropeptides/neurotransmitters. As recent epidemiological studies have associated peripheral progesterone levels with suicide risks in humans, we mapped PR distribution in the human hypothalamus in relation to age and sex and characterized its (co-) expression in specific cell types. The infundibular nucleus (INF) appeared to be the primary hypothalamic structure via which progesterone modulates stress-related neural circuitry. An elevation of the number of pro-opiomelanocortin+ (POMC, an endogenous opioid precursor) neurons in the INF, which was due to a high proportion of POMC+ neurons that co-expressed PR, was related to suicide in patients with mood disorders (MD). MD donors who died of legal euthanasia were for the first time enrolled in a postmortem study to investigate the molecular signatures related to fatal suicidal ideations. They had a higher proportion of PR co-expressing POMC+ neurons than MD patients who died naturally. This indicates that the onset of endogenous opioid activation in MD with suicide tendency may be progesterone-associated. Our findings may have implications for users of progesterone-enriched contraceptives who also have MD and suicidal tendencies

A diurnal rhythm of stimulatory input to the hypothalamo-pituitary-adrenal system as revealed by timed intrahypothalamic administration of the vasopressin V1 antagonist

The mammalian suprachiasmatic nuclei (SCN) contain an endogenous pacemaker that generates daily rhythms in behavior and secretion of hormones. We hypothesized that the SCN imposes its circadian rhythm on the rest of the brain via a rhythmic release of its transmitters in its target areas. Previously, we demonstrated a pronounced inhibitory effect of vasopressin (VP), released from SCN terminals in the dorsomedial hypothalamus, on the release of the adrenal hormone corticosterone. In the present study, microdialysis-mediated intracerebral administration of the VP V1-receptor antagonist was used to pursue the study of the mechanisms underlying the circadian control of basal corticosterone release. Using timed administrations of the VP antagonist divided equally over the day/night cycle, we were able to uncover the existence of an additional stimulatory input from the SCN to the hypothalamopituitary-adrenal (HPA) axis. Peak activity of this stimulatory SCN input takes place during the second half of the light period, after the daily peak of VP secretion, with a delay of approximately 4-6 hr. In all likelihood, the inhibitory and stimulatory circadian input via separate mechanisms affects corticosterone release. Together, these two opposing circadian control mechanisms of the HPA axis enable a precise timing of the circadian peak in corticosterone releas

Restricted daytime feeding modifies suprachiasmatic nucleus vasopressin release in rats

The authors have shown previously that vasopressin (VP) release from suprachiasmatic nucleus (SCN) efferents in rats is important for the timing of the circadian activity of the hypothalamo-pituitary-adrenal (HPA) axis, resulting in a circadian rise in corticosterone at dusk. When meals are supplied at a fixed time during the light period, however, this normal circadian activity of the HPA axis is strongly modified. Under such a restricted feeding regimen, a corticosterone peak appears just before the daily meal in addition to the circadian corticosterone peak at dusk. This feeding-associated rise in corticosterone is regarded as an SCN-independent circadian rhythm because it is sustained in SCN-lesioned animals. Despite these previous results, the authors investigated a putative involvement of SCN-derived VP in the control of the prefeeding corticosterone peak by measuring the intranuclear release of VP in the SCN and plasma corticosterone levels in rats in ad libitum feeding conditions as well as in animals that were obliged to feed during a 2-h period in the middle of the light period. Restricted daytime feeding caused clear changes in the daily release pattern of VP from SCN terminals. Both a delayed onset of the diurnal rise and a premature decline of the elevated daytime levels were observed, but the acrophase of the VP rhythm was not phase shifted. Concerning the circadian corticosterone peak, no phase shift of its acrophase was observed either. It is concluded that (1) restricted daytime feeding does affect SCN activity, (2) intranuclear release of VP within the SCN is an important mechanism to amplify and synchronize the circadian rhythms as dictated by the light/dark-entrained circadian pacemaker, and (3) VP release observed in animals on restricted feeding is completely compatible with the previously proposed inhibitory action of SCN-derived VP on the HPA axi

Novel environment induced inhibition of corticosterone secretion: physiological evidence for a suprachiasmatic nucleus mediated neuronal hypothalamo-adrenal cortex pathway

Basal plasma ACTH and corticosterone levels are controlled by the suprachiasmatic nucleus (SCN), the site of the circadian pacemaker, resulting in a daily peak in plasma corticosterone and ACTH. The present study was carried out to investigate the mechanisms employed by the biological clock to control these hormones. Novel environment induced changes in plasma ACTH and corticosterone in intact and SCN-lesioned animals were employed as experimental approach. Placing intact animals in a new environment results in different plasma corticosterone and ACTH responses depending on the clock time of the stimulus. (1) Novel environment (2 h after onset of darkness (ZT14)) results in a fast decrease followed by an increase in corticosterone. This changing pattern in corticosterone secretion was not accompanied by any change in plasma ACTH, suggesting a direct neuronal control of the adrenal cortex. (2) In contrast, novel environment at 2 h after light onset (ZT2) results in a rapid increase in plasma ACTH. Regression analysis of the relation ACTH-corticosterone before and after stress shows a changed pattern at ZT2, although at that time still no significant correlation between ACTH and corticosterone was detected. AT ZT14 this correlation was only present after stress. (3) SCN lesioning results in low basal ACTH at all circadian times combined with elevated corticosterone levels. Here, a new environment results in an immediate increase in corticosterone without inhibition; ACTH also increases rapidly, but attains lower levels than at ZT2 in intact animals. (4) The present results therefore demonstrate SCN modulating corticosterone secretion by affecting ACTH secretion and changing the sensitivity of the adrenal cortex by means of a neuronal inpu

A diurnal rhythm of stimulatory input to the hypothalamo-pituitary-adrenal system as revealed by timed intrahypothalamic administration of the vasopressin V1 antagonist

The mammalian suprachiasmatic nuclei (SCN) contain an endogenous pacemaker that generates daily rhythms in behavior and secretion of hormones. We hypothesized that the SCN imposes its circadian rhythm on the rest of the brain via a rhythmic release of its transmitters in its target areas. Previously, we demonstrated a pronounced inhibitory effect of vasopressin (VP), released from SCN terminals in the dorsomedial hypothalamus, on the release of the adrenal hormone corticosterone. In the present study, microdialysis-mediated intracerebral administration of the VP V1-receptor antagonist was used to pursue the study of the mechanisms underlying the circadian control of basal corticosterone release. Using timed administrations of the VP antagonist divided equally over the day/night cycle, we were able to uncover the existence of an additional stimulatory input from the SCN to the hypothalamopituitary-adrenal (HPA) axis. Peak activity of this stimulatory SCN input takes place during the second half of the light period, after the daily peak of VP secretion, with a delay of approximately 4-6 hr. In all likelihood, the inhibitory and stimulatory circadian input via separate mechanisms affects corticosterone release. Together, these two opposing circadian control mechanisms of the HPA axis enable a precise timing of the circadian peak in corticosterone releas

GABA release from suprachiasmatic nucleus terminals is necessary for the light-induced inhibition of nocturnal melatonin release in the rat

The daily rhythm of melatonin production in the mammalian pineal is driven by the endogenous circadian pacemaker in the suprachiasmatic nuclei. The major release period of melatonin is closely linked to the dark phase of the 24-h day/night cycle. Environmental light will affect melatonin release in two ways: (i) it entrains the rhythm of the circadian oscillator; and (ii) it causes an acute suppression of nocturnal melatonin release. These two effects of light are both mediated by the suprachiasmatic nucleus and enable the pineal gland to convey information about day length to the reproductive system through changes in melatonin levels. Glutamate is currently believed to be the major transmitter in the retinal ganglion cell fibers reaching the suprachiasmatic nucleus. At present no information is available, however, about the transmitter(s) implicated in the further propagation, i.e. from the suprachiasmatic nucleus onwards, of the light information. In the present study we provide evidence that the endogenous release of GABA from suprachiasmatic nucleus terminals is implicated in the further transmission of light information to the pineal gland. Bilateral administration of the GABA-antagonist bicuculline to hypothalamic target areas of the suprachiasmatic nucleus completely prevents the inhibitory effect of nocturnal light on melatonin secretion and the present study thus documents that retina-mediated photic activation of suprachiasmatic nucleus neurons induces the release of GABA from efferent suprachiasmatic nucleus nerve terminals, resulting in an inhibition of melatonin release by the pineal gland. Together with our previous (electro)physiological data these results identify GABA as an important mediator of rapid synaptic transmission of suprachiasmatic nucleus output to its target area

Estrogen receptors and metabolic activity in the human tuberomamillary nucleus: changes in relation to sex, aging and Alzheimer's disease

The human tuberomamillary nucleus (TMN), that is the sole Source of histamine in the brain, is involved in arousal, learning and memory and is impaired in Alzheimer's disease (AD) as shown by the presence of cytoskeletal alterations, a reduction in the number of large neurons, a diminished neuronal metabolic activity and decreased histamine levels in the hypothalamus and cortex. Experimental data and the presence of sex hormone receptors Suggest an important role of sex steroids in the regulation of the function of TMN neurons. Therefore, we investigated sex-, age- and Alzheimer-related changes in estrogen receptor alpha and beta (ERalpha and ERbeta) in the TMN. In addition, metabolic activity changes of TMN neurons were determined by measuring Golgi apparatus (GA) and cell size. In the present study, ERalpha immunocytochemical expression in AD patients did not differ from that ill elderly controls. However, a larger amount of cytoplasmic ERbeta was found in the TMN cells of AD patients. Earlier studies, using the GA size as a parameter, have shown a clearly decreased metabolic activity in the TMN neurons in AD. In the present study, the size of the GA did not change during aging, indicating the absence of strong metabolic changes. Cell size of the TMN neurons appeared to increase during normal aging in men but not ill women. Concluding, the enhanced cytoplasmic expression of ERbeta in the TMN may be involved in the diminished neuronal metabolism of these neurons in AD patients. (C) 2003 Elsevier B.V. All rights reserve